The clinical course and outcome of HIV-1 infection are highly variable among individuals, depending on a combination of viral, host, and environmental determinants. Genetic resistance to HIV-1 clearly involves a complex array of host genetic effects involving variants that have subtle but significant consequences on gene expression or protein function. Overall, the strongest genetic associations with HIV-1 disease progression have involved the HLA class I loci, which appear to influence resistance/susceptibility to AIDS in a highly multifarious manner through both acquired and innate immune responses. The effects of HLA on outcome to HIV-1 exposure and infection have been studied more thoroughly than those pertaining to any other infectious disease. Many of the associations reported have not been confirmed in multiple studies, but consistent patterns of susceptibility or resistance conferred by certain HLA class I alleles or genotypes have emerged. HLA-B*35 has been the most consistently implicated allotype in susceptibility to AIDS progression in Caucasian individuals. In order to address the potential functional significance of this genetic association, we performed high-resolution typing of HLA class I among 559 Caucasian and 210 African American seroconverters, dividing the B*35 subtypes into two groups based on peptide-binding specificity. This algorithm demonstrated that the susceptibility effect of B*35 is attributable only to the subtypes that preferentially bind a broad set of antigenic epitopes (and perhaps with less affinity) relative to the B*35 subtypes that do not associate with AIDS progression. In collaboration with Dr. Xia Jin, we showed that although the overall magnitude of cytotoxic T lymphocytes (CTL) responses did not differ between patients with susceptible vs. neutral B*35 subtypes, a negative association between CTL activity and viral load was consistently observed for neutral subtypes, whereas no such relationship was observed for the susceptible B*35 subtypes. The data suggested that higher levels of virus-specific CTL contribute to protection against HIV disease progression among individuals with neutral subtypes, but not in those with susceptible B*35 subtypes. HLA class I molecules have also been shown to participate in innate immune responses as ligands for killer immunoglobulin-like receptor (KIR) molecules expressed on natural killer (NK) cells and a subset of CD8+ cells. NK cells defend against viral infections by producing cytokines and killing virally infected cells, functions that are regulated by activating and inhibitory KIR molecules through recognition of specific class I allotypes on target cells. Like HLA, the KIR locus is extremely diverse in terms of the number and types of genes present on a given haplotype. We hypothesized that the KIR and HLA loci, which are unlinked, may interact in a synergistic manner, given their receptor-ligand relationship. HLA-B alleles encoding the Bw4 epitope have been associated with delayed progression to AIDS and we tested whether this relationship could be due to a functional interaction between the activating receptor gene, KIR3DS1, and alleles encoding its potential ligands, a subset of the HLA-B Bw4 alleles. Genetic analysis of our HIV-1 infected seroconverters supported a model involving a protective epistatic interaction between KIR3DS1 and Bw4 subtypes that is most pronounced early after HIV infection, consistent with a defensive role for NK cells in the innate immune response soon after infection. We also plan to study the potential influence of several polymorphic immune response genes on HIV-1 infection, progression to AIDS, and development of specific AIDS-defining illnesses (these include Kaposi's sarcoma, lymphoma, pneumocystis pneumonia, mycobacterium infection, and other opportunistic infections). The studies will include: 1) an extension of previous studies addressing effects of HLA; 2) analyses of KIR haplotypic and allelic effects that will take into account functionally relevant combinations of HLA and KIR genetic variants; and 3) identification of potential MICA and MICB allelic effects. Virtually all seroconverters (patients who had enrolled in at-risk AIDS cohort studies when their HIV-1 antibody status was negative and subsequently became HIV-1 antibody positive), all high-risk seronegative patients (those who are at high risk for HIV-1 infection based on a history of likely chronic exposure, but remain HIV-1 negative), and a subset of seroprevalent patients (those who were HIV-1 antibody-positive before enrollment) from six cohorts have now been typed using high-resolution methods for HLA class I and II. Typing for the presence/absence of KIR genes and subtyping of KIR3DL1 is nearly complete in our seroconverter and high-risk seronegative samples. A typing system for MICA has been established and we are in the process of typing this gene in the AIDS cohorts as well. A few studies have examined the relationship between HLA and the risk of HIV-1 infection, primarily involving individuals from Africa. Effects of HLA on highly active anti-retroviral therapy (HAART) are only just being considered and nearly all studies of HLA on progression to AIDS have been performed in men. To address these deficiencies in our understanding of HIV-1 pathogenesis, we have recently established a collaboration with Dr. Howard Strickler and the Women's Interagency Health Study (WIHS) to investigate effects of immune response genes on three disease outcomes to HIV-1 exposure: 1) risk of becoming infected in groups of HIV+ and HIV- individuals matched for site of enrollment and risk factors; 2) progression to AIDS from specific ranges of baseline CD4 counts and viral loads; and 3) response to HAART. The WIHS cohort is the largest multicenter prospective cohort study of HIV and its complications in women, involving individuals with high rates of hepatitis C virus (HCV) and human papilloma virus (HPV) infection (see below). The cohort has enrolled about 4,000 women of varied ethnic backgrounds in the U.S. and detailed clinical data is collected on the participants every six months. Patients participating in the WIHS will be typed for HLA class I, class II, and KIR. Genotyping of the MIC genes is also being considered for future studies. Using the largest sample size reported to date (231 individuals with HCV clearance and 444 matched persistently infected individuals), we studied the effects of HLA class I alleles on HCV clearance/persistence. Interestingly, HLA-B*57, an allele that shows strong protection against HIV-1 disease progression, was also protective in terms of HCV clearance. Likewise, the Cw*04-B*5301 haplotype associates with disease susceptibility in terms of both HIV disease progression and HCV persistence. The functional mechanisms of these similarities between HLA associations with HIV-1 and HCV may be quite distinct, but such comparisons across different diseases provide insight into the dynamic selection processes that govern variability in HLA allele frequencies. A number of studies have suggested that HLA diversity is an important determinant in progression to HPV-associated cervical neoplasia. Further refinement of these studies is required to define more precisely the genetic effects of HLA on HPV disease since the reported data lack corroboration to a large extent. In order to test comprehensively the relationship between HLA class I and development of cervical neoplasia among individuals infected with HPV, we performed high-resolution typing of 1,321 individuals participating in three large disease studies.